An ALPS-like patient without an identified mutation has been found to have a unique in vitro defect in T cell apoptosis associated with IL-2 withdrawal but normal T cell and B cell apoptosis in response to staurosporine, etoposide, cisplatin and radiation as well as a normal Fas pathway induction of apoptosis. The defect in this patient appears to be particularly associated with the development of lymphoid malignancy as this individual has developed two distinct lymphoid tumors. This suggests the possibility of a distinct defect in the mitochondrial cell death pathway with a number of candidate proteins that were evaluated and expression microarrays were set-up ultimately leading to the identification of a gain of function defect in NRAS. This also defines an that this intrinsic pathway of cell death serves as an alternative pathway for cytokine withdrawl induced lymphocyte apoptosis and suggests that the Fas mediated extrinsic pathway may actually play a more minor role in this. We have now studied a total of three patients with somatic NRAS mutations all of whom have defects in T cell apoptotic death associated with cytokine withdrawl. The important clincial observation is that all three patients presented early in childhood with a disorder that has many features of acute myelomonocytic leukemia (AMML) but it is not an aggressive or malignant disorder unlike AMML. In fact the marked monocytosis and bone marrow changes improve without therapy while AMML requires bone marrow transplantation. This distinction is obviously of great clinical importance and we are now fielding additional patient samples in order to better define this somatic NRAS mutation disorder that overlaps with ALPS. The results of these expanded studies will be reported upon completion of the intial studies.